Cholecystokinin (CCK) is a polypeptide hormone found in both the periphery and the brain that plays a major role in gut function, in the digestive process and in the control of feeding behaviors. Relative to other neuropeptides, high concentrations of CCK and CCK receptors are found in the brain and CCK meets many of the criteria for consideration as a neurotransmitter (J. F. Rehfeld, J. Neurochem, 1985, 448:1-8), suggesting important CNS functions for this peptide. CCK exists in multiple biologically active forms (CCK-58, CCK-39, CCK-33, CCK-8 and CCK-4), with CCK-33, CCK-8 and CCK-4 predominating in the periphery (J. Martinez in Comprehensive Medicinal Chemistry, Vol. 3, J. C. Emmett, ed, Pergamon Press, Oxford, England, 1990, p. 925) and the C-terminal octapeptide, CCK-8, predominating in the brain.
CCK has a variety of regulatory roles in the periphery including gallbladder contraction and pancreatic enzyme secretion (V. Mutt in Gastrointestinal Hormones, G. B. J. Glass, ed, Raven Press, New York, 1980, p. 169; J. A. Williams, Biomed. Res., 1982, 3:107), inhibition of gastric emptying and suppression of food intake. CCK and its fragments are believed to play an important role in appetite regulation and satiety (Della-Fera, Science 1979, 206:471; Saito et al., Nature 1981, 289:599; and Smith, Eating and Its Disorders, A. J. Stunkard and E. Stellar, eds., Raven Press, New York, 1984, p. 67) and recently, patients with bulimia were shown to have lower than normal CCK levels in their plasma (Geracioti et al., New England Journal of Medicine, 1988, 319:683). An additional role for CCK in the periphery is to regulate the release of insulin. CCK has been shown to increase the levels of insulin when administered to mammals (Rushakoff et al., J. Clin. Endocrinol. Metab. 1987, 65:395).
CCK in the brain has been suggested to have a role in schizophrenia (N.P.V. Nair et al, Prog. Brain Res., 1986, 65:237), memory and cognition (S. Itoh and H. Lal, Drug Dev. Res., 1990, 21:257), and CCK antagonists have been suggested to be potentially useful in drug abuse therapy (B. Costall et al. in "Proceedings of the Cambridge Symposia, The Neurological Basis of Anxiety," Robinson College, Cambridge, U.K., Sep. 7 and 8, 1990).
Two sub-types of the CCK receptor have been identified. Type-A CCK receptors, commonly referred to as the "peripheral-type" receptor, are primarily found in the pancreas, gall bladder, ileum and on vagal afferent nerve fibers. Type-A CCK receptors bind CCK-8 with high affinity but have low affinity for desulfated CCK-8 and CCK-4. The brain contains predominantly the Type-B receptors that bind CCK-8, desulfated CCK-8 and CCK-4 with high affinity. Type-A CCK receptors are found in the brain, although in low abundance (D. R. Hill et al., Brain Res, 1988, 454:101-5; D. R. Hill et al., Neurosci Lett., 1988, 89:133-9; R. W. Barrett et al., Mol. Pharmacol, 1989, 36:285-90; and D. R. Hill et al., J. Neurosci, 1990, 10:1070-81), and play an important role there also (V. Dauge et al., Pharmacol Biochem Behav., 1989, 34:157-63; J. Soar et al., Pharmacol. Biochem. Behav, 1989, 33:637-40). Type-A receptor-selective CCK agonists are currently of particular interest as potential anorectic agents because of the ability of CCK-8 and Type-A CCK-selective agonists to suppress food intake in several animal species (Della-Fera et al., Science, 1979, 206:471; K. E. Asin et al., Intl Conference on Obesity., 1990, Abstract p. 40).
Obesity is a major disorder affecting as much as one third of the North American population. Several studies have shown that such individuals are at increased risk in developing cardiovascular disease (hypertension and hypercholesterolemia), diabetes and several types of cancer. The effective treatment of obesity, however, remains a largely unachieved goal. Existing phamacotherapeutic approaches to weight loss involve the use of amphetamine-based agents such as amphetamine, diethylpropion, mazindol and fenfluramine which act directly on the CNS to lower food intake by modulating dopaminergic, adrenergic and/or serotonergic mechanisms. Although weight loss can be achieved with such agents, their use is restricted due to CNS side-effects, potential addiction liability and the production of tolerance to their actions, with chronic administration leading to potential depression, vestibular disturbances, hallucinations and addiction, as well as interference with the actions other drugs such as MAO inhibitors and antihypertensives. There is also a subpopulation of obese patients that is refractory to present anorectic drug treatments. The medical need is high for an effective anorectic agent which overcomes the above disadvantages of existing therapies. Of particular need are agents which act by alternative mechanisms to modulate food intake and/or metabolism.
Several references have disclosed CCK agonists or analogs of CCK-8. For example, U.S. Pat. No. 4,490,364, issued Dec. 25, 1984 to Rivier, discloses heptapeptide, octapeptide and nonapeptide analogs of CCK-8 as CCK agonists for stimulating gallbladder contractions, arresting the secretion of gastric acid and treating convulsions. J. D. Rosamond in European Patent Application EP381,340, published Aug. 8, 1990, and in European Patent Application EP268,297, published May 25, 1988, discloses hepta- and octapeptides with sulfate ester groups which are useful for treating obesity.
C-terminal fragments of CCK have recently been reported to function as CCK receptor antagonists or gastrin receptor antagonists (Jensen et al., Biochem. Biophys. Acta, 1983, 757:250; Spanarkel, J. Biol. Chem. 1983, 258:6746). Japanese Patent Application 45/10506 to Miyao et al., discloses a tetrapeptide derivative of the carboxy terminal sequence of gastrin (L-Trp-L-Lys-L-Asp-L-PheNH.sub.2) which act as antagonists of gastrin.
In contrast, the present invention relates to tetrapeptide analogs which function as agonists of CCK Type-A receptor activity. These CCK agonists are useful in the treatment and prevention of CCK-related disorders of the gastrointestinal, appetite and insulin regulatory systems of animals, especially man. They are also useful as central nervous system suppressants which can exhibit antipsychotic, neuroleptic, anxiolytic, and anticonvulsant effects, among other effects on central nervous system disorders.